title: Bone marrow-derived smooth muscle-like cells are infrequent in advanced primary atherosclerotic plaques but promote atherosclerosis.
abstract: OBJECTIVE
  Although vascular smooth muscle cells (VSMCs) provide the major structural integrity of atherosclerotic plaques, their origin has been questioned. In particular, although some studies identified plaque VSMCs originating from bone marrow or peripheral blood, their frequency is controversial and their function unknown. We used genetic tracking of cell fate through smooth muscle cell (SMC)-specific LacZ reporter activity and VSMC-selective apoptosis to investigate the frequency, distribution, and role of marrow-derived VSMCs in atherogenesis.
  
  
  RESULTS
  Cultured mouse bone marrow-derived smooth muscle-like cells expressed SMC markers and functional SMC promoter-driven transgenes over time. Transplantation of apolipoprotein E (ApoE)(-/-) mice with smooth muscle myosin heavy chain-Cre/ROSA26R/ApoE(-/-) marrow showed that 0.7±0.14% cells expressed LacZ in atherosclerotic plaques, located superficially in early plaques, and in necrotic cores but not fibrous caps of advanced lesions. Cells expressing both progenitor and SMC markers showed a similar distribution and frequency. Apoptosis of marrow-derived SMC-like cells transplanted from SM22α-human diphtheria toxin receptor/ApoE(-/-) mice retarded atherogenesis, with reduced plaque macrophage content. Cultured marrow-derived SMC-like cells secreted proinflammatory cytokines and promoted macrophage migration, VSMC proliferation, and collagen synthesis.
  
  
  CONCLUSIONS
  Bone marrow-derived SMC-like cells are infrequent in advanced primary atherosclerotic plaques and absent in fibrous caps. However, these cells secrete proinflammatory cytokines and mitogens and promote atherosclerosis.
authors.affiliation: Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Haixiang
authors.initials: H
authors.lastname: Yu
authors.forename: Victoria
authors.initials: V
authors.lastname: Stoneman
authors.forename: Murray
authors.initials: M
authors.lastname: Clarke
authors.forename: Nichola
authors.initials: N
authors.lastname: Figg
authors.forename: Hong-Bo
authors.initials: HB
authors.lastname: Xin
authors.forename: Michael
authors.initials: M
authors.lastname: Kotlikoff
authors.forename: Trevor
authors.initials: T
authors.lastname: Littlewood
authors.forename: Martin
authors.initials: M
authors.lastname: Bennett
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000209:etiology* / Q000473:pathology; D001854:Bone Marrow Cells / Q000502:physiology*; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D004167:Diphtheria Toxin / Q000494:pharmacology; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*
chemical_list: D001057:Apolipoproteins E; D004167:Diphtheria Toxin; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins